A study in rodents examining the differences in hepatic gene expression and overall lipid metabolism between male and female rats has reported that there are large-scale changes in the genes regulating lipid metabolism in female but not male rodents after vertical sleeve gastrectomy (VSG). The study also found that VSG caused less export of triglycerides in a fasting state in females while lipid uptake and export are not changed by VSG in males. The paper, ‘Bariatric surgery emphasizes biological sex differences in rodent hepatic lipid handling’, was published in the journal Biology of Sex Differences.

It is already known that response to metabolic stress, such as weight loss or exercise, fat is mobilised more readily in women, and transcriptional profiling of hepatic genes has shown that 70% of 1,249 genes were upregulated in females and many of those genes were related to lipid metabolism. The authors state that if we are to understand the molecular changes underlying the success of surgery, we cannot ignore the potential influence of sex on the affected pathways.

The researchers from University of Mississippi Medical Center, the University of Michigan, the University of Cincinnati and the Hospital Infantil de México “Federico Gómez” note that the majority of preclinical studies are in male rodents despite the fact 80% percent of bariatric patients are female. Therefore, they wanted to directly compare hepatic lipid metabolism in virgin male and female rats after VSG.

Two cohorts of age-matched virgin male and female Long-Evans rats were placed on a high fat diet for three weeks and then received either sham or VSG. Cohort 1 (male, n = 6; female, n = 6 rats) was studied for hepatic microarray gene expression after surgery while cohort 2 (male, n = 20 and female, n = 20 rats) was studied for the phenotypic response to surgery.

Outcomes

The outcomes revealed that each sex exhibited significantly decreased body weight due to a reduction in fat mass relative to Sham controls (p<0.05). Microarray and follow-up qPCR on liver revealed striking sex differences in gene expression after VSG that reflected a down-regulation of hepatic lipid metabolism and an up-regulation of hepatic inflammatory pathways in females vs. males after VSG.

While the males had a significant reduction in hepatic lipids after VSG, there was no reduction in females. Ad lib-fed and fasting circulating triglycerides, and postprandial chylomicron production were significantly lower in VSG relative to Sham animals of both sexes (p < 0.01). However, hepatic VLDL production, highest in sham-operated females, was significantly reduced by VSG in females but not males.

They found that both male and female rats lost a significant amount of body weight in the first 31 days after VSG and remained at a reduced body weight until they were terminated at the end of the study (main effect of surgery, p<0.001 and time p<0.001). Following VSG, males exhibited a transient reduction in lean body mass at 4 weeks postoperatively (student’s t test, p<0.01) that was no longer significant at week 16.

For females, there was no significant difference in lean body mass at any time point between surgical groups. Both males and females had a significantly lower body fat mass at 4 and 16 weeks after VSG vs. sham surgeries (p<0.001). The absolute change in body fat mass was less in females as compared to males likely due to the comparatively smaller pre-surgical fat mass.

During postoperative week 5, both male and female VSG animals had significantly reduced fasting blood glucose (main effect of surgery, p<0.01) and females overall had reduced glucose levels in comparison to males (main effect of sex, p<0.001). After VSG, males had significantly reduced glucose levels 45 and 60 min after glucose gavage compared to Sham animals (surgery × time, p<0.001). Glucose response to the oral glucose gavage was not significantly different between sham and VSG surgeries at any time point in the females.

Both male and female VSG animals had significantly reduced plasma triglycerides in an ad lib fed state and at 4, and 8h of fasting, compared to the Sham animals (surgery × time interaction, p<0.0001). By 24-h of fasting, all groups had similar levels of triglycerides.

Basal levels of plasma triglycerides were greatest in sham surgery males compared to all other groups (p<0.01) and following the gavage of a radiolabeled lipid emulsion lead to there were similar increases in plasma triglycerides in the in males and females regardless of surgery.

n the liver, and independent of surgery, females had significantly greater 3H uptake than males (main effect of sex, p<0.001). However, surgery did not alter the amount of 3H-glycerol trioleate uptake into the liver, gastrocnemius, or gonadal fat (epididymal for male and peri-ovarian for females) tissues but did cause a significant increase of 3H-glycerol trioleate in subcutaneous fat of VSG compared to Sham males (p<0.05).

Sham females had significantly greater VLDL production compared to all other groups and importantly, VSG lowered this to the level of males at 4 and 6h. Likewise, the rate of triglyceride appearance over time was significantly reduced by VSG in females but not males (sex × surgery interaction, p<0.001). The authors data suggest that hepatic triglyceride export is slowed by VSG in females.

“Here, we find that bariatric surgery emphasizes sex differences specifically in hepatic lipid handling such that genes that regulate lipid metabolism are down-regulated by VSG resulting in lower VLDL export and maintenance of sham-level hepatic triglycerides,” they write. “This is in contrast to the surgery-induced reduction in hepatic triglycerides by VSG in males which is not explained by changes in lipid uptake or export and likely is reflected by intrahepatic changes in metabolism.”

“In our efforts to understand the molecular underpinnings of bariatric surgery, research has mostly neglected the contribution of sex to outcomes,” the authors conclude. “The current results demonstrate that studying female rodents is necessary to advance our understanding of the molecular mechanisms of bariatric surgery for the greater than 80% of bariatric surgery patients that are female.”